Multiple myeloma is a hematological B cell malignancy. The vast majority of the affected cells are localized within the bone marrow, where they promote bone destruction and impair normal hematopoiesis. Improved methods in stem cell therapies and novel drugs such as proteasome inhibitors and derivatives of thalidomide have lead to significant improvement in overall survival of myeloma patients, which currently stands at about five years. Nevertheless, multiple myeloma remains incurable and its clinical cause is usually characterized by good initial response to treatment followed after some time by relapse and an eventual development of general resistance to current therapies.
It has been demonstrated that the heat shock protein 70 (Hsp70) plays an essential pathogenic role in multiple myeloma. In recent years, increasing evidence has suggested Hsp70 as a potential anti-cancer target. It has been previously observed that dual targeting of the Hsp70 isoforms Hsp72 and Hsp73 induces tumor-specific apoptosis. However, to date only a limited number of Hsp70 inhibitors is available, while efficient and selective pharmacological agents are almost completely missing.
US 2009/0068144 A1 discloses tetrahydroisoquinolin-1-one derivatives for the treatment of cancer. The exemplified compounds bear a 4-carboxylic acid substituent being present as free acid or for example as —CONH lower alkyl moiety.
US 2005/0124614 A1 discloses 3,4-dihydroisoquinolin-1-ones that are said to be activators of caspases and inducers of apoptosis. Most of the exemplified compounds bear no or only small substituents, like methyl or propyl at position 2 of the tetrahydroisoquinolinone ring. Furthermore, the carboxamide substituent at position 4 may bear relatively small substituents like hydrogen and alkyl.
US 2010/0227866 A1 discloses a broad variety of tetrathydroisoquinolin-1-one derivatives which are said to be useful as therapeutic agents for irritable bowel syndrome.
There is therefore still a need for further compounds exhibiting improved Hsp70 protein inhibiting activity and being useful for the treatment of cancer, in particular of multiple myeloma.